Podocyte proliferation and de-differentiation are the hallmarks of the collapsing glomerulopathy associated with HIV- associated nephropathy. Transgenic mice with podocyte specific overexpression of the VEGF-164 isoform have been shown to develop a collapsing FSGS, which simulates the classic renal lesion seen in HIVAN. This finding suggests a critical role of podocyte-secreted VEGF in the development of collapsing FSGS. Our preliminary data show an increase in VEGF expression in podocytes from HIVAN as compared to normal podocytes and that VEGF stimulation can cause podocyte proliferation and de-differentiation. The plan of this project is to study the role of VEGF in normal and HIV-infected podocytes using conditionally immortalized podocyte lines. The goal is also to determine how HIV genes regulate VEGF expression in podocytes and to determine which signaling pathways are involved and how they may interact with known pathways including nef, Src/STAT3. Also, we hope to investigate whether VEGF inhibitors can improve the kidney disease in HIV-1 (TG26) transgenic mice as this could open up a new avenue in the treatment of HIV. [unreadable] [unreadable] [unreadable]